Process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine

ABSTRACT

A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3-5-diamine (lamotrigine) of the formula I:                    
     2,3-Dichloronitrobenzene in C 1 -C 6  aliphatic alkanol is hydrogenated at 55-90 psi gas pressure using metal catalyst at 27-35° C. 2,3-Dichloroaniline is diazotised and cyano-de-diazonised with metal cyanide at 65-80° C. 2,3-Dichlorobenzonitrile is hydrolysed and 2,3-dichlorobenzoic acid is chlorinated at 55-130° C. Cyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried out with a metal cyanide and alkali metal iodide by refluxing in an aprotic solvent under an inert atmosphere. 2,3-Dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonate in an organic solvent in acidic conditions using catalyst at 90-125° C. followed by insitu cyclisation of the Schiff&#39;s base by refluxing in an aliphatic alkanol with base. Crude lamotrigine is purified.

TECHNICAL FIELD

This invention relates to a process for the preparation of6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine of the formula I:

commonly known as Lamotrigine.

Lamotrigine, an anti-epileptic drug, elicits its action by suppressingseizures by inhibiting the release of excitatory neurotransmitters.Lamotrigine presently offers a worthwhile alternative for treatingpatients suffering from nitractable partial seizures coupled with orwithout secondary generalised seizures and therefore shows goodpotential for broader applications in other areas of epilepsymanagement.

BACKGROUND ART

One method of preparation of lamotrigine of the formula I involvesreaction of 6-(2,3-dichlorophenyl)-5-chloro-3-thiomethyl 1,2,4-triazineof the formula II:

with ethanolic ammonia in a sealed tube at 180° C./250 psi pressure (PCTPublication No WO 96/20935). This process is time consuming (˜72hours)and also produces lamotrigine in low yields because of which it is notcommercially viable.

Another route for the synthesis of lamotrigine of the formula I involvesphotochemical reaction of the compound of the formula III:

where R=CN or CONH₂, using ultraviolet or visible radiation in thepresence of a base in an alkanol solvent and also heating when R=CN (PCTPublication No WO 96/20934). The preparation of the compound of theformula III involves expensive and hazardous reagents. Further,undesired by-products like the de-aminated hydroxy derivative oftriazine formed during the photochemical reaction demand elaborateseparation and purification techniques, thereby making this routelengthy and tedious, besides producing low yields of lamotrigine (<10%).Therefore this process is not Able for industrial scale manufacture oflamotrigine.

Yet another method for the synthesis of lamotrigine of the formula Iinvolves cyclisation of the Schiff's base of the formula IV:

by refluxing in C₁-C₄ aliphatic alkanol in the presence or absence of astrong base such as KOH (EP Patent No 21121 and U.S. Pat. Nos 4,602,017and 4,847,249).

The Schiff's base of the formula IV may be prepared by a sequence ofsteps comprising:

(1) reaction of 2,3-dichloroiodobenzene of the formula V:

with magnesium, followed by reaction of the resulting Grignard moeitywith solid carbondioxide;

(2) reaction of the resulting 2,3-dichlorobenzoic acid of the formulaVI:

with thionyl chloride in an inert atmosphere such as moisture freenitrogen gas;

(3) reaction of the resulting 2,3-dichlorobenzoyl chloride of theformula VII:

with a metal cyanide and alkali metal iodide such as Cu(one)CN and KI inthe presence of an organic solvent such as xylene in an inert atmospheresuch as nitrogen; and

(4) reaction of the resulting 2,3-dichlorobenzoylcyanide of the formulaVIII:

with aminoguanidine bicarbonate in an organic solvent such as DMSO inaqueous acidic medium using 8N HNO₃. The purification of crudelamotrigine of the formula I thus obtained by cyclisation of theSchiff's base of the formula IV is carried out by recrystallisation fromisopropanol (FP Patents Nos 59987 and 21121 and U.S. Pat. Nos 4,602,017and 3,637,688).

The formation of 2,3-dichlorobenzoic acid of the formula VI for thepreparation of the Schiff's base of the formula IV by the above routedemands a dry environment thereby making the process laborious. Thesereactions leading to the Schiff's base of the formula IV also employexpensive and hazardous reagents like DMSO in large quantities andxylene. The conversion of 2,3-dichlorobenzoyl chloride to2,3-dichlorobenzoyl cyanide takes 96 hours thereby making the entireprocess for the synthesis of the Schiff's base from 2,3-dichlorobenzoylchloride time consuming (˜7.5-10 days). This route also produces lowyields of lamotrigine (˜10%). Therefore this process for the preparationof lamotrigine is not feasible for industrial scale manufacture.

The Schiff's base of the formula IV may also be prepared by the reactionof 2,3-dichlorobenzoyl cyanide of the formula VIII with aminoguanidinebicarbonate in the presence of acetonitrile and dilute aqueous sulfuricacid (U.S. Pat. No 4,847,249). This route for the synthesis of theSchiff's base is reported to produce low yields of lamotrigine.

As lamotrigine has emerged to be one of the promising anti-epileptic andanti-convulsant for treating CNS disorders, its commercial productionassumes significance. Despite the several routes known for the synthesisof lamotrigine there is still need for a route which is safe,convenient, efficient, economical and less time consuming.

DISCLOSURE OF THE INVENTION

An object of the invention is to provide a process for the preparationof 6-(2,3-dichlorophenyl)-1,2,4-triazine -3,5-diamine of the formula I,commonly known as lamotrigine, which is safe and convenient.

Another object of the invention is to provide a process for thepreparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine of theformula I, commonly known as lamotrigine, which is less time consuming.

Another object of the invention is to provide a process for thepreparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine -3,5-diamine of theformula I commonly known as lamotrigine, which is efficient andeconomical.

Another object of the invention is to provide a process for thepreparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine of theformula I, commonly known as lamotrigine, which is suitable forindustrial scale manufacture.

According to the invention, there is provided a process for thepreparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine -3,5-diamine of theformula I:

commonly known as lamotrigine which comprises:

a) reduction of 2,3-dichloronitrobenzene of the formula IX:

in C₁-C₆ aliphatic alkanol with hydrogen gas at a pressure of 55-90 psiin the presence of a metal catalyst at 27-35° C.;

b) diazotisation of the resulting 2,3-dichloroaniline of the formula X:

with sodium nitrite and a mineral acid at −5° to 5° C. followed bycyano-de-diazonation with a metal cyanide at 65-80° C.;

c) hydrolysis of the resulting 2,3-dichlorobenzonitrile of the formulaXI:

under acidic or alkaline conditions;

d) chlorination of the resulting 2,3-dichlorobenzoic acid of the formulaVI:

with a chlorinating agent at 55-130° C.;

e) cyano-de-halogenation of the resulting 2,3-dichloro-benzoyl chlorideof the formula VII:

with a metal cyanide in the presence of an alkali metal iodide byrefluxing in an aprotic solvent under an inert atmosphere;

f) condensation of the resulting 2,3-dichlorobenzoyl cyanide of theformula VIII:

with aminoguanidine bicarbonate in an organic solvent in acidicconditions in the presence of a catalyst at 90°-125° C. followed byinsitu cyclisation of the resulting Schiff's base of the formula IV:

by refluxing in an aliphatic alkanol in the presence of a base; and

g) purification of the resulting crude lamotrigine of the formula I:

by a known method such as recrystallisation from an aliphatic alkanol orchromatographic separation

The reduction of 2,3-dichloronitobenzene may be carried out bydissolution of 2,3-dichloronitrobenzene preferably in methanol. Thepressure of the hydrogen gas for reduction may be preferably 50-70 psi,still preferably 80 psi and the temperature for the reduction may bepreferably 30° C. The metal catalysts used in the reduction reaction maybe nickel, Raney nickel platinum oxide, rhodium-platinum oxide,palladium-carbon, or palladium salts, preferably Raney nickel. An alkalior alkaline earth metal hydroxide such as NaOH, KOH, Ca(OH)₂ or Mg(OH)₂may be optionally used in the reduction reaction.

For the diazotisation of 2,3-dichloroaniline, mineral acids such as HClor H₂SO₄, preferably H₂SO₄, may be used. The diazotisation may becarried out preferably at 0° C. The excess sodium nitrite may beoptionally decomposed using agents such as urea, sulfamic acid or asmall amount of a primary amine dissolved in acid.

The cyano-de-diazonation reaction may be carried out using metalcyanides such as NaCN, KCN or Cu(one)CN or a mixture thereof. Preferablya mixture of Cu(one)CN and NaCN may be used. The cyano-de-diazonationmay be carried out preferably at 65° C. Excess of cyanide may beoptionally decomposed using sodium hypochlorite solution. A phasetransfer catalyst such as crown ether or a quaternary ammonium salt inthe presence of a nickel catalyst may be optionally used during thecyano-de-diazonation reaction.

The alkaline hydrolysis of 2,3-dichlorobenzonitrile may be carried outusing NaOH or KOH in the presence of an aliphatic alkanol such asmethanol or ethanol. Preferably methanolic NaOH at reflux temperaturesmay be used. The unreacted cyano compound may be extracted usingtoluene, ethyl acetate or a mixture of toluene and ethyl acetate,preferably toluene. Mineral acids such as H₂SO₄ or HCl may be used foracidic hydrolysis.

2,3-dichlorobenzoic acid may be chlorinated using SOCl₂ PCl₃ or PCl₅.Preferably SOCl₂ at 80° C. is used.

The cyano-de-halogenation reaction of 2,3-dichlorobenzoyl chloride iscarried out under an inert atmosphere such as nitrogen atmosphere. Themetal cyanide used may be Cu(one)CN, NaCN, KCN or a mixture of Cu(one)CNand NaCN. The alkali metal iodide may be NaI or KI. Preferably Cu(one)CNin the presence of KI may be used. The aprotic solvent for the reactionmay be monochlorobenzene, xylene or any other aprotic solvent,preferably monochlorobenzene.

The condensation of 2,3-dichlorobenzoyl cyanide with aminoguanidinebicarbonate is carried out in the presence of a catalyst such asp-toluenesulfonic acid or a lewis acid catalyst such as AlCl₃, TiCl₄,FeCl₃, ZnCl₂, ZrCl₄ or any protonated acid such as HCl or H₂SO₄, in anorganic solvent such as toluene or ethyl benzene, in acidic medium usingHCl, HNO₃ or H₂SO₄. Preferably toluene and H₂SO₄ with p-toluenesulfonicacid at 100-120° C. may be used. Insitu cyclisation of the Schiff's basemay be carried out in an aliphatic alkanol such as methanol with astrong base such as NaOH, KOH or NaOMe. Preferably methanol and NaOMemay be used.

For the recrystallisation of the crude lamotrigine, an aliphatic alkanolsuch as isopropanol ethanol or methanol, preferably methanol may beused.

Pharmaceutically acceptable acid addition salts of lamotrigine of theformula I may be prepared by treating lamotrigine of the formula I withacids such as hydrochloric, sulphuric, citric, tartaric, phosphoric,lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic,methane sulphonic, p-toluenesulphonic or benzenesulphonic acid.

According to the invention a new route is employed in the preparation oflamotrigine of the formula I. The substrate for the preparation thereofviz 2,3-dichloronitrobenzene and also the other reagents of the processof the invention are safe, inexpensive and easily available, thuseliminating the use of hazardous and expensive reagent reported in theprior art. The reactions leading to 2,3-dichlorobenzoic acid need not becarried out in a dry environment. Also chlorination of2,3-dichloro-benzoic acid is conveniently carried out in a non-inertatmosphere without affecting the efficiency of the process. The use ofcatalyst during reduction of 2,3-dichloronitrobenzene at roomtemperature proceeds without dehalogenation thereby giving increasedyield and purity of 2,3-dichloroaniline. Also the other intermediates ofthe process of the invention are obtained in good yields and purity. Theconversion of 2,3-dichlorobenzoyl chloride to 2,3-dichlorobenzoylcyanide requires about 6 hours, as against 96 hours reported in aprocess of the prior art. Similarly the preparation of the Schiff's basefrom 2,3-dichlorobenzoyl chloride and further instiu cyclisation of theSchiff's base to lamotrigine also is less time consuming (8 hrs), as a7.5-10 days reported in the prior art processes to prepare the Schiff'sbase itself. Therefore, the process of the invention is less timeconsuming and economical. The process of the invention gives a yield of23% of lamotrigine (starting from 2,3-dichloronitrobenzene) as against ameagre yield of 10% (from 2,3-dichloroiodobenzene) reported in the priorart. Lamotrigine by our invention is also obtained with an excellentpurity of 99.67%(by HPLC) after recrystallisation. The process of theinvention is, therefore, efficient and economical and also suitable forindustrial scale manufacture.

The following experimental example is illustrative of the invention butnot limitative of the scope thereof.

EXAMPLE 1 Preparation of 2,3-dichloroaniline (C₆H₃Cl₂NH₂)

2,3-Dichloronitrobenzene (800 g, 4.17 moles) was dissolved in methanol(5.6 L) and charged into an autoclave. Raney nickel (80 g, 10% w/w) wasadded to the solution. The reaction mixture was hydrogenated at 80 psifor 3.5 hrs at 30° C. and filtered through celite. Methanol wasdistilled off to give 2,3-dichloroaniline (C₆H₃Cl₂NH₂).

Yield = 656 g Purity = 98% (when analysed by Gas Chromatography)

Preparation of 2,3-dichlorobenzonitrile (C₆H₃Cl₂CN)

Conc. H₂SO₄ (1.365 L) and water (4.5 L) were charged into a suitableround bottom flak and the solution was cooled to 0° C.2,3-Dichloroaniline (650 g, 4.012 moles) was added to the above solutionand the reaction mixture was cooled and maintained at 0° C. A saturatedsolution of sodium nitrite (332.22 g, 4.815 moles) was added dropwise tothe reaction while maintaining the temperature below 5° C. The reactionmixture was stirred at 0-5° C. for 1 hr and neutralised with sodiumhydroxide at 0-5° C. The neutral solution was added dropwise to thecyanide solution [Cyanide solution obtained by mixing Cu(one)CN (365 g,4.10 moles), NaCN (340 g 6.93 moles) and water (1.0 L)] at 65° C., undervigorous stirring for a period of 15 mins. The reaction mixture waswarmed to 70° C. and stirred for another 15 mins. The2,3-dichlorobenzonitrile so formed was extracted using ethylacetate (2.0L). The organic layer was died over sodium sulfate and stripped to givea semi-solid mass of 2,3-dichlorobenzonitile (C₆H₃Cl₂CN).

Yield = 650 g Purity = 92% (when analysed by Gas Chromatography).

Preparation of 2,3-dichlorobenzoic Acid (C₆H₃Cl₂COOH)

Sodium hydroxide (168.0 g, 4.2 moles, 1.2 eq) was dissolved in a mixturecontaining methanol (1.08 L) and water (600 ml) maintained at 5-10° C.This solution was then added to a flask containing2,3-dichlorobenzonitrile (602.0 g, 3.5 moles). The reaction mixture washeated and refluxed for 10 hrs with slow stream of air bubbles beingpurged into the reaction mixture. Methanol was distilled off and water(1.0 L) was added to the reaction mixture. The reaction mixture wasextracted with toluene (2×500 ml). The toluene fraction containingunreacted cyano compound was concentrated and recycled. The aqueousportion was treated with conc. HCl (32%/, 800 ml) to obtain a whitesolid preciptate of 2,3-dichlorobenzoic acid(C₆H₃Cl₂COOH) which wasfiltered and dried.

Yield = 500 g Purity = 97% (when analysed by High Performance LiquidChromatography)

Preparation of 2,3-dichlorobenzoyl Chloride (C₆H₃Cl₂COCl)

2,3-Dichlorobenzoic acid (500 g, 2.618 moles) was charged into a 2 Lfour necked round bottom flask containing thionyl chloride (623 g, 5.235moles) and heated at 80° C. for 1.0 hr to give 2,3-dichlorobenzoylchloride(C₆H₃Cl₂COCl), after removal of excess of thionyl chloride.

Yield = 500 g Purity = 98% (when analysed by Gas Chromatography)

Preparation of 2,3-dichlorobenzoyl Cyanide (C₆H₃Cl₂COCN)

Copper cyanide (215 g, 2.4 moles), potassium iodide (199 g, 1.2 moles)and monochlorobenzene (1.0 L) were added to a 3 L four necked roundbottom flask containing 2,3-dichlorobenzoyl chloride (500g, 2.392moles). The reaction mixture was heated to reflux under nitrogen blanketand maintained at 132-135° C. for 6 hrs. The reaction mixture was thenfiltered and monochlorobenzene distilled off to obtain2,3-dichlorobenzoyl cyanide(C₆H₃Cl₆COCN).

Yield = 470 g Purity = 97% (when analysed by Gas Chromatography)

Preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(C₉H₇Cl₂N₅)

Aminoguanidine bicarbonate (136 g, 1.0 mole) and toluene (1 L) werecharged into a 3 L four necked round bottom flask. To this slurry wasadded conc sulfuric acid (98 g, 1.0 mole) in a slow stream and p-toluenesulfonic acid (25 g). The mixture was stirred for 15 mins and heated to110° C. Water was azeotroped out from the mixture and the reactionmixture was cooled to 80° C. To this, 2,3-dichlorobenzoyl cyanide (100g, 0.5 mole) was added the reaction mixture was refluxed for 3.5 hrs.Toluene was removed completely and the reaction mixture was cooled to25° C. To it was added sodium methoxide (500 g) (solution methanol 25%w/w) and refluxed for 3 hrs. Methanol was removed completely and thereaction mixture was cooled to 20° C. Water (400 ml) was added to thereaction mixture and stirred at 20-25° C. for 1 hr. The precipitatedsolid was filtered and washed with water till free of base to give crude6-2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (C₉H₇Cl₂N₅).

Yield = 72 g Purity = 94% (when analysed by High Performance LiquidChromatography)

The crude product was recrystallised from methanol to give pure6-(2,3-dichlorophenyl)-1,2,4triazine-3,5-diamine(C₉H₇Cl₂N₅).

Yield = 64 g Purity = 99.7% (when analysed by High Performance LiquidChromatography).

What is claimed is:
 1. A process for the preparation of6-(2,3-dichlorophenyl)-1,2,4-triazine -3,5-diamine of the formula I:

commonly known as lamotrigine which comprises: a) reduction of2,3-dichloronitrobenzene of the formula IX:

in C₁-C₆ aliphatic alkanol with hydrogen gas at a pressure of 55-90 psiin the presence of a metal catalyst at 27-35° C.; b) diazotisation ofthe resulting 2,3-dichloroaniline of the formula X:

with sodium nitrite and a mineral acid at −5° to 5° C. followed bycyano-de-diazonation with a metal cyanide at 65-80° C.; c) hydrolysis ofthe resulting 2,3-dichlorobenzonitrile of the formula XI:

under acidic or alkaline conditions; d) chlorination of the resulting2,3-dichlorobenzoic acid of the formula VI:

with a chlorinating agent at 55-130° C.; e) cyano-de-halogenation of theresulting 2,3-dichloro-benzoyl chloride of the formula VII:

with a metal cyanide in the presence of an alkali metal iodide byrefluxing in an aprotic solvent under an inert atmosphere; f)condensation of the resulting 2,3-dichlorobenzoyl cyanide of the formulaVIII:

with aminoguanidine bicarbonate in an organic solvent in acidicconditions in the presence of a catalyst at 90-125° C. followed byinsitu cyclisation of the resulting Schiff's base of the formula IV:

by refluxing in an aliphatic alkanol in the presence of a base; and g)purification of the resulting crude lamotrigine of the formula I:

by a known method such as recrystallisation from an aliphatic alkanol orchromatographic separation.
 2. A process as claimed in claim 1, whereinthe reduction of 2,3-dichloronitrobenzene is carried out in methanolusing hydrogen gas at a pressure of 80 psi in the presence of Raneynickel at 30° C.
 3. A process as claimed in claim 1, wherein thediazotisation of 2,3-dichloroaniline is carried out using sodium nitriteand H₂SO₄ at 0° C.
 4. A process as claimed in claim 1, wherein thecyano-de-diazonation is carried out using a mixture of Cu(one)CN andNaCN at 65° C.
 5. A process as claimed in claim 1, wherein thehydrolysis of 2,3-dichlorobenzonitrile is carried out by refluxing withmethanolic NaOH.
 6. A process as claimed in claim 1, whereinchlorination of 2,3-dichlorobenzoic acid is carried out with SOCl₂ at80° C.
 7. A process as claimed in claim 1, wherein thecyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried outwith Cu(one)CN and KI in monochlorobenzene under nitrogen atmosphere at132-135° C.
 8. A process as claimed in claim 1, wherein2,3-dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonatein toluene in the presence of sulphuric acid and p-toluene sulfonic acidat 100-120° C.
 9. A process as claimed in claim 1, wherein insitucyclisation of the schiff's base is carried out in methanol in thepresence of NaOMe.
 10. A process as claimed in claim 1, wherein crudelamotrigine is purified by recrystallisation from methanol.